title: Disruption of the expression of the proprotein convertase PC7 reduces BDNF production and affects learning and memory in mice.
abstract: PC7 belongs to the proprotein convertase family, whose members are implicated in the cleavage of secretory precursors. The in vivo function of PC7 is unknown. Herein, we find that the precursor proBDNF is processed into mature BDNF in COS-1 cells coexpressing proBDNF with either PC7 or Furin. Conversely, the processing of proBDNF into BDNF is markedly reduced in the absence of either Furin or PC7 in mouse primary hepatocytes. In vivo we observe that BDNF and PC7 mRNAs are colocalized in mouse hippocampus and amygdala and that mature BDNF protein levels are reduced in these brain areas in PC7 KO mice but not in the hippocampus of PC1/3 KO mice. Various behavioral tests reveal that in PC7 KO mice spatial memory is intact and plasticity of responding is mildly abnormal. Episodic and emotional memories are severely impaired, but both are rescued with the tyrosine receptor kinase B agonist 7,8-dihydroxyflavone. Altogether, these results support an in vivo role for PC7 in the regulation of certain types of cognitive performance, in part via proBDNF processing. Because polymorphic variants of human PC7 are being characterized, it will be important in future studies to determine their effects on additional physiological and behavioral processes.
authors.affiliation: Departments of Psychiatry and Behavioral Sciences, Cell Biology, and Neurobiology, Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University Medical Center, Durham, NC 27710.
authors.forename: William C
authors.initials: WC
authors.lastname: Wetsel
authors.forename: Ramona M
authors.initials: RM
authors.lastname: Rodriguiz
authors.forename: Johann
authors.initials: J
authors.lastname: Guillemot
authors.forename: Estelle
authors.initials: E
authors.lastname: Rousselet
authors.forename: Rachid
authors.initials: R
authors.lastname: Essalmani
authors.forename: Il Hwan
authors.initials: IH
authors.lastname: Kim
authors.forename: Jesse C
authors.initials: JC
authors.lastname: Bryant
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Marcinkiewicz
authors.forename: Roxane
authors.initials: R
authors.lastname: Desjardins
authors.forename: Robert
authors.initials: R
authors.lastname: Day
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Constam
authors.forename: Annik
authors.initials: A
authors.lastname: Prat
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
mesh_terms: D000679:Amygdala / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005260:Female; D044950:Flavanones / Q000494:pharmacology; D015870:Gene Expression; D057809:HEK293 Cells; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology*; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013381:Subtilisins / Q000235:genetics / Q000378:metabolism*
chemical_list: C478869:7,8-dihydroxyflavanone; D019208:Brain-Derived Neurotrophic Factor; D044950:Flavanones; D011498:Protein Precursors; D012333:RNA, Messenger; C490930:Pcsk7 protein, mouse; D013381:Subtilisins
keywords: BDNF processing; PC7 substrates; brain phenotypes; fear conditioning; gene knockout